PROTACs, especially ER degraders, suggest a potential strategy for addressing endocrine resistance in advanced ER + breast cancer, as reflected in encouraging preliminary clinical data. This integrated analysis highlights the rapid translation of this technology while underscoring the critical need to expand target scope, address inherent resistance mechanisms, and broaden applications to other breast cancer subtypes. Our article synthesizes current knowledge and trial landscape, thereby providing a consolidated foundation to inform future research and clinical development of PROTACs in breast cancer.

The May 1 approval of vepdegestrant, the first PROTAC drug to earn regulatory clearance, establishes targeted protein degradation as a clinically validated therapeutic modality. For patients with ESR1-mutant advanced breast cancer, it offers a new therapeutic option after standard hormone-based regimens have failed. And for the broader field, it is proof of concept for a pipeline of protein-destroying drugs that now numbers in the dozens.

Notably, the ERα degrader vepdegestrant (ARV-471) achieved positive Phase III results in the VERITAC-2 trial, demonstrating significant progression-free survival benefit in ESR1-mutant ER+/HER2- breast cancer, marking a milestone for PROTAC clinical translation...Emerging technologies such as lysosome-targeting chimeras (LYTAC) and next-generation E3 ligases expand the druggable target space. With over 30 PROTACs currently in clinical trials across oncology, this review provides a comprehensive analysis of PROTAC applications in breast cancer and outlines future directions for precision medicine.

P1/2, N=11, Active, not recruiting, Pfizer | Trial completion date: Apr 2026 --> Dec 2026 | Trial primary completion date: Apr 2026 --> Dec 2026

P3, N=624, Active, not recruiting, Pfizer | N=219 --> 624

P1/2, N=217, Completed, Arvinas Estrogen Receptor, Inc. | Active, not recruiting --> Completed

P1, N=24, Recruiting, Pfizer | Not yet recruiting --> Recruiting

On June 6, 2025, Arvinas and Pfizer submitted a New Drug Application (NDA) for vepdegestrant to the U.S. Food and Drug Administration (FDA), representing an important step in the clinical translation of PROTAC technology. This review summarizes the design, synthesis, degradation mechanism, preclinical pharmacology, and clinical development of vepdegestrant and discusses the broader implications and future prospects of oral PROTAC-based ER degraders in breast cancer therapy.

P1/2, N=71, Active, not recruiting, Pfizer | Trial completion date: Mar 2026 --> Sep 2026

Coadministration of multiple doses of carbamazepine 200 mg, a strong CYP3A4 inducer, with a single dose of vepdegestrant 200 mg resulted in a modest (36%) decrease in plasma vepdegestrant exposure. A single dose of vepdegestrant 200 mg was well tolerated in healthy adult participants.

P1/2, N=37, Active, not recruiting, Pfizer | Trial completion date: Mar 2026 --> Sep 2026 | Trial primary completion date: Mar 2026 --> Sep 2026

Coadministration of multiple doses of itraconazole, a strong CYP3A4 inhibitor, increased vepdegestrant exposure by 69%, suggesting the involvement of CYP3A4-mediated metabolism, albeit not predominantly, in vepdegestrant elimination.